The applicant's long-term goals are (1) to establish himself as an independent clinician-scientist in the field of oral cancer (OCSCC) biology and (2) to develop a research program that focuses on investigating the molecular mechanisms of tumor progression. To achieve these goals, a hypothesis-driven analysis of the role of TrkB in OCSCC is proposed by the applicant, which will also integrate a balanced program of intense mentorship and research training. The central hypothesis is that dysregulated TrkB signaling directly upregulates OCSCC invasion, resulting in aggressive tumor behavior and metastasis. Preliminary data show that TrkB is overexpressed in OCSCC and that TrkB is a mediator of the invasive phenotype in OCSCC. The central hypothesis will be tested by first determining the molecular mechanisms of TrkB-mediated invasion and migration in OCSCC. The applicant will then examine the role of TrkB in tumor progression and metastasis in animal models of OCSCC using non-invasive imaging modalities. The applicant will then define the predictive value of TrkB expression as a biomarker of aggressive behavior and adverse outcome among patients with OCSCC. The proposed work will demonstrate the opportunistic resurrection of an embryologically critical ligand-receptor system in OCSCC tumor biology. Upregulation of TrkB may serve as a potential escape mechanism for tumors that become resistant to traditional and novel therapies in OCSCC, thereby offering a potential therapeutic target for patients suffering from epithelial cancers. The career development program will integrate comprehensive laboratory-based research training with didactic coursework and scientific mentorship. These experiences will allow the applicant to achieve his career goals of evolving into an independent scientific investigator in an outstanding scientific environment. PUBLIC HEALTH RELEVANCE: OCSCC remains a significant public health problem, accounting for over 2% of all cancer-related deaths in the US, and the overall survival for this disease has not been significantly altered in the past 30 years. Our preliminary evidence demonstrates that TrkB is important for the development and progression of this cancer. The global aims of this grant are to explore how TrkB contributes to cancer progression and to establish TrkB as a target for novel therapies to treat patients with this devastating and deadly cancer.